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NAM Annual Meeting: Cancer, can we beat the oddsPanel 2, Monday October 15, 2018
Resistance to Cancer Immunotherapy
Antoni Ribas, M.D., Ph.D.Professor of Medicine, Surgery, Molecular and Medical Pharmacology
Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC)Director, Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA
University of California Los Angeles (UCLA)Chair, Melanoma Committee at SWOG
Disclosures of Relevant Relations with Industry:Consultant – Honoraria: Amgen, BMS, Chugai, Genentech, Merck, Novartis, Roche
Scientific Advisory Board – Stock: Advaxis, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Merus, Rgenix
Co-founder – Stock: Lutris, PACT Pharma, Tango Therapeutics
Cancer immunotherapy: When the CD8 T cell is the drug
Baseline
Baseline
Day +180
Day + 90
Pre-CD8+ T-cell infiltrate
Post-CD8+ T-cell infiltrate
Cases from:Bartosz Chmielowski, MD, PhD, UCLAWen-Jen Hwu, MD, MD Anderson Cancer Center
Hamid et al. NEJM 2013Eroglu et al. Nature 2018
IHC Analysis of CD8+ T-cells in samples obtained before and during anti-PD1 treatment Tumeh et al. Nature 2014
PD1/PDL1
PD1/PDL1
Melanoma response to PD-1 blockade is mediated by pre-existing infiltrates of CD8s inhibited by reactively expressed PD-L1
Tumor cell
T cell
Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M
B2MMHC class I
TCR-α TCR-βIFN-γ
P P
IFNGR2
JAK2JAK1
PD-L1
PD-1
GASP
P
Anti-Proliferative Pro-Apoptotic Genes
TAP 1/2 LAMP PSMB 8,9,10
CXCL 9,10,11
MHC
ICAM-1
IFNGR1
STAT1STAT1
PD-L1IRF1
Graphics by Khriszha Quema-Yee
Tumor cell
T cell
Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M
B2M
TCR-α TCR-βIFN-γ
P P
IFNGR2
JAK2JAK1
PD-L1
PD-1
GASP
P
Anti-Proliferative Pro-Apoptotic Genes
TAP 1/2 LAMP PSMB 8,9,10
CXCL 9,10,11
MHC
ICAM-1
IFNGR1
STAT1STAT1
PD-L1IRF1
MHC class I
Timeline of clinical development of approved immune checkpoint inhibitors
Ribas and Wolchok, Science 2018Anti-PD-1/L1: 6 agents approved in 11 cancer indications in 4 years
Tumor cell
T cell
Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M
B2M
TCR-α TCR-βIFN-γ
P P
IFNGR2
JAK2JAK1
PD-L1
PD-1
GASP
P
Anti-Proliferative Pro-Apoptotic Genes
TAP 1/2 LAMP PSMB 8,9,10
CXCL 9,10,11
MHC
ICAM-1
IFNGR1
STAT1STAT1
PD-L1IRF1
PD-1 resistance biopsy data:Zaretsky… Ribas, NEJM 2016Sade-Feldman… Hacohen, Nature Comm 2017Gettinger… Politi, Cancer Discovery 2017
MHC class I
CRISPR screen:Manguso… Haining, Nature 2017Patel… Restifo, Nature 2017Pan… Wucherpfennig, Science 2018
Tumor cell
T cell
Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M
B2MMHC class I
TCR-α TCR-βIFN-γ
P P
IFNGR2
JAK2JAK1
PD-1
IFNGR1
PD-1 resistance biopsy data:Zaretsky… Ribas, NEJM 2016Shin… Ribas, Cancer Discovery 2017Sucker… Paschen, Nature Comm2017
CRISPR screen:Manguso… Haining, Nature 2017Patel… Restifo, Nature 2017Pan… Wucherpfennig, Science 2018
GASP
P
Anti-Proliferative Pro-Apoptotic Genes
TAP 1/2 LAMP PSMB 8,9,10
CXCL 9,10,11
MHC
ICAM-1
STAT1STAT1
PD-L1IRF1
PD-L1
Precision cancer immunotherapy
Anti-PD-1/anti-PD-L1
Generate T cells
+ anti-CTLA4 or other checkpoints+ immune activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ immune suppressor cell inhibitors+ standard cancer therapies
Bring T cells into tumors
VaccinesTCR engineered ACTCAR engineered ACT
Modified from Ribas, Cancer Discovery 2016
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